JOURNAL OF VIROLOGY
·
2026
·
IF 4.1
Huiying Zhang,Yihan Liu,Ting Xu,Junwen Luan,Leiliang Zhang
Hepatitis C virus (HCV) entry is a critical step in establishing infection and is highly dependent on host cell co-receptors. We previously identified that the tight junction protein CLDN12 facilitates HCV entry. However, the regulatory mechanisms governing the dynamic post-translational modifications of CLDN12 remain unclear. This study employs targeted mutagenesis, palmitoylation level analysis, plasma membrane localization, manipulation of key enzymes, and functional virology assays to reveal whether and how reversible palmitoylation regulates the function of CLDN12 in HCV entry. We found that the palmitoylation occurs at cysteine residues C3 and C109 of CLDN12, a modification critical for its role in mediating HCV entry. The palmitoyltransferase ZDHHC7 is a key enzyme that catalyzes the palmitoylation of CLDN12, positively promoting HCV entry. Acyl-protein thioesterases APT1 and APT2 regulate the de-palmitoylation of CLDN12 through differential modulation at the two sites, thereby negatively regulating HCV entry. Our study discovers that ZDHHC7 and APT1/2 form a reversible palmitoylation switch, which regulates the efficiency of HCV entry by dynamically controlling the plasma membrane localization of CLDN12. This finding reveals a new mechanism by which HCV exploits the host’s palmitoylation cycle to promote infection, and highlights this regulatory axis as a potential target for antiviral intervention.
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DOI
PubMed
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Xue Huang,Jia Yao,Lu Liu,Jing Chen,Ligang Mei,Jingjing Huangfu,Dong Luo,Xinyi Wang,Changhai Lin,Xiaorong Chen,Yi Yang,Sheng Ouyang,Fujing Wei,Zhuolin Wang,Shaolin Zhang,Tingxiu Xiang,Dante Neculai,Qiming Sun,Eryan Kong,Edward W. Tate,Aimin Yang
p62 is a well-characterized autophagy receptor that recognizes and sequesters specific cargoes into autophagosomes for degradation. p62 promotes the assembly and removal of ubiquitinated proteins by forming p62-liquid droplets. However, it remains unclear how autophagosomes efficiently sequester p62 droplets. Herein, we report that p62 undergoes reversible S -acylation in multiple human-, rat-, and mouse-derived cell lines, catalyzed by zinc-finger Asp-His-His-Cys S -acyltransferase 19 (ZDHHC19) and deacylated by acyl protein thioesterase 1 (APT1). S -acylation of p62 enhances the affinity of p62 for microtubule-associated protein 1 light chain 3 (LC3)-positive membranes and promotes autophagic membrane localization of p62 droplets, thereby leading to the production of small LC3-positive p62 droplets and efficient autophagic degradation of p62-cargo complexes. Specifically, increasing p62 acylation by upregulating ZDHHC19 or by genetic knockout of APT1 accelerates p62 degradation and p62-mediated autophagic clearance of ubiquitinated proteins. Thus, the protein S -acylation-deacylation cycle regulates p62 droplet recruitment to the autophagic membrane and selective autophagic flux, thereby contributing to the control of selective autophagic clearance of ubiquitinated proteins.
研究领域:
细胞生物学
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分子生物学
·
自噬
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PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 7
·1518
·
IF 6.525
Mengchen An,Mengxiao Shi,Jingjing Su,Yueru Wei,Rongrong Luo,Pengchao Sun,Yongxing Zhao
Although the inhibitors of the interleukin-6 receptor (IL-6R) and tumor necrosis factor-α (TNF-α) have achieved a certain success in the clinical treatment of rheumatoid arthritis (RA), great effort should be made to overcome side effects and to improve patient compliance. The present research aimed to address these problems by the co-delivery of tocilizumab (TCZ)—an inhibitor of IL-6R—and an aptamer Apt1-67, which specifically inhibits TNF receptor 1 via separable microneedles (MN). MN were featured with a sustained release of TCZ from needle tips and a rapid release of Apt1-67 from needle bodies by using methacrylate groups grafted hyaluronic acid as the fillings of needle tips and polyvinyl alcohol/polyvinyl pyrrolidone as the fillings of needle bodies. Our results demonstrated that TCZ and Apt1-67 were distributed in MN as expected, and they could be released to the surroundings in the skin. In vivo studies revealed that combined medication via MN (TCZ/[email protected]) was superior to MN loaded with a single drug. Compared with subcutaneous injection, TCZ/[email protected]was of great advantage in inhibiting bone erosion and alleviating symptoms of CIA mice. This study not only provides a novel approach for combined medication with different release properties but also supplies a strategy for improving drug efficacy.Keywords:separable microneedles;tocilizumab;aptamer Apt1-67;rheumatoid arthritis
研究领域:
药学
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生物医学工程
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风湿病学
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产品关联
DOI
PubMed
高影响因子
CHEMBIOCHEM
·
2021
·Vol. 22
·期 11
·1948-1954
·
IF 3.164
Yaoyao Hou,Jianjun Hou,Xixia Liu
Graphical Two very different DNA aptamers have been reported for dopamine, one derived from an RNA aptamer (named Apt1) and other obtained via direct aptamer selection (named Apt2). In this study, we used four homogeneous binding assays to compare these two DNA dopamine aptamers. Apt1 does not appear to be able to bind dopamine specifically, while Apt2 showed specific binding and could be used for developing related biosensors. Dopamine is an essential neurotransmitter and its detection is important for bioanalytical chemistry. Two very different DNA aptamers have been reported for dopamine, one derived from an RNA aptamer (named Apt1) and other obtained via direct aptamer selection (named Apt2). In this study, we used four homogeneous binding assays to compare these two DNA dopamine aptamers. Thiazole orange (TO) fluorescence assay indicated that the Apt2 specifically bound with dopamine with a K d of 2.37 μM, which was consistent with that from the isothermal titration calorimetry (ITC) assay. However, Apt1 had much less TO fluorescence change and also no signal from ITC. By labeling the two ends of the two aptamers by a fluorophore and a quencher, the aptamer beacons showed binding of dopamine only for Apt2. Finally, the label-free AuNP-based colorimetric assay showed no difference between these two aptamer sequences, and even non-binding random DNA showed the same response, indicating that AuNPs were not a good probe for detecting dopamine. According to the data, Apt1 does not appear to be able to bind dopamine specifically, while Apt2 showed specific binding and could be used for developing related biosensors.
研究领域:
分析化学
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生物化学
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生物传感器开发
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PubMed
高影响因子
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